Oncostatin M and the interleukin-6 and soluble interleukin-6 receptor complex regulate alpha1-antichymotrypsin expression in human cortical astrocytes.
alpha1-Antichymotrypsin (ACT) is an acute phase protein expressed in the brain which specifically colocalizes with amyloid-beta during Alzheimer's disease. We analyzed ACT synthesis in cultured human cortical astrocytes in response to various cytokines and growth factors. Oncostatin M (OSM) and interleukin (IL)-1beta were potent stimulators of ACT mRNA expression, whereas tumor necrosis factor-alpha had modest activity, and IL-6 and leukemia inhibitory factor (LIF) were ineffective. The finding that OSM, but not LIF or IL-6, stimulated ACT expression suggests that human astrocytes express a "specific" OSM receptor, but not IL-6 or LIF receptors. However, cotreatment of human astrocytes with soluble IL-6 receptor (sIL-6R).IL-6 complex did result in potent stimulation of ACT expression. When the human ACT gene was cloned, two elements binding STAT1 and STAT3 (signal transducer and activator of transcription) in response to OSM or IL-6.sIL-6R complexes could be identified and characterized. Taken together, these findings indicate that OSM or IL-6.sIL-6 complexes may regulate ACT expression in human astrocytes and thus directly or indirectly contribute to the pathogenesis of Alzheimer's disease.
Kordula
T
T
Institute of Molecular Biology, Jagiellonian University, 31-120 Kraków, Poland.
Rydel
R E
RE
Brigham
E F
EF
Horn
F
F
Heinrich
P C
PC
Travis
J
J
D000209:Acute-Phase Proteins / Q000096:biosynthesis; D000544:Alzheimer Disease / Q000209:etiology; D001253:Astrocytes / Q000187:drug effects*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D003001:Cloning, Molecular; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000032:analysis; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008969:Molecular Sequence Data; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000209:Acute-Phase Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D015850:Interleukin-6; C508351:OSM protein, human; D010455:Peptides; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D053683:Oncostatin M; D002918:Chymotrypsin